Abnormal hyperphosphorylation of tau plays an important role in Alzheimer's disease (AD) and other tauopathies. Current therapeutic approaches with focus on tau kinases (e.g. GSK-3, MAPK, cdk5, CK-1, PKA, CaMKII) are hindered by multiple and redundant tau phosphorylation pathways. In contrast, protein phosphatase-2A (PP2A) is the major tau phosphatase accounting for ~70% of tau dephosphorylation, and recent research shows that its expression and activity are down-regulated in AD. PP2A activity is governed by reversible carboxyl-methylation, thus inhibiting demethylation might be a promising intervention strategy to restore healthy tau phosphorylation levels. Building a screening platform around this hypothesis, we identified a small molecule SIG1012, which reduces p-tau levels in N2a cells in a dose-dependent manner and is orally efficacious in reducing p-tau in wild type mice. Preliminary pharmacological data suggests that SIG1012 has highly favorable safety and toxicology profiles. The proposed Phase I research plan is critical to validating PP2A as a pharmaceutical target for effective intervention in AD by a small molecule. It outlines specific steps for the proposed proof of concept studies of efficacy in animal models of AD. The critical 3xTg-AD mouse and (AAV)-I2 CTF rat experiments will be carried out in collaboration with Dr. Khalid Iqbal, a world- renowned expert on the role of tau in neurodegenerative diseases. Successful completion of this research proposal will lead in Phase II to formal preclinical development of SIG1012 as the "first-in-class" PP2A modulating agent for treatment of AD and other tauopathies. ) PUBLIC HEALTH RELEVANCE: Alzheimer's disease (AD) is a progressive and fatal brain disease that afflicts over 5 million Americans today and over 27 million people worldwide. Current treatments of AD are largely unsatisfactory and development of more effective therapies represents a great unmet medical need. Successful development of this novel class of phosphoprotein modulators will provide an important additional, and potentially better, therapeutic option for people suffering from AD.